Rethinking Obesity Through the Lens of Lipid Spillover.

Abstract

Conventional models frame obesity as excess caloric intake but do not explain why cardiometabolic disease develops in only a subset of individuals. Building on Unger's seminal lipotoxicity hypothesis and subsequent adipose expandability frameworks, the lipid spillover concept emphasizes adipose tissue dysfunction-rather than total fat mass-as the driver of disease. When subcutaneous adipose tissue reaches its safe storage capacity, adipocyte hypertrophy, inflammation, and insulin resistance increase lipolysis, raising circulating free fatty acids and promoting ectopic lipid deposition. Accumulation of fat in organs such as the liver, heart, skeletal muscle, pancreas, vasculature, and kidneys initiates organ-specific injury and systemic metabolic-vascular dysfunction that may occur independently of body mass index. Visceral, perivascular, and epicardial fat depots act as inflammatory reservoirs that exacerbate vascular disease and myocardial dysfunction. Advances in imaging and biomarker profiling now enable quantification of ectopic fat burden and activity, supporting risk stratification beyond body size alone. Therapeutic strategies that preferentially reduce ectopic fat through lifestyle intervention, pharmacotherapy, or bariatric surgery, offer targeted cardiometabolic risk reduction.Copyright © 2026 The Authors.